Persons with HIV on combination antiretroviral therapy (cART) are at increased risk of the premature development of age-associated non-communicable comorbidities (AANCC), including cardiovascular, chronic kidney, liver and pulmonary disease, diabetes mellitus, osteoporosis, non-AIDS associated malignancies, and neurocognitive impairment. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated ageing. The underlying pathogenesis is likely to be multifactorial and include sustained immune activation, both systemically and within the central nervous system.
By building on an established infrastructure for conducting longitudinal HIV cohort studies in Amsterdam and London, we will provide a detailed, prospective evaluation of AANCC among HIV-infected patients suppressed on cART and appropriately chosen and comparable non-infected controls. In this way, we will provide a robust estimate of the effect of treated HIV infection on the prevalence, incidence and age of onset of AANCC, thus clearly establishing a link between HIV and AANCC.
COBRA’s main objectives and underlying sub objectives are:
1) To establish the link between HIV infection and age-associated non-communicable co-morbidities (AANCC).
2) To determine and compare the prevalence, incidence and outcomes of AANCC, including neurocognitive co-morbidity, in a cohort of middle-aged HIV-infected subjects with sustained HIV suppression on cART and similarly aged HIV-uninfected subjects, through comprehensive clinical and laboratory diagnostic means.
3) To elucidate and clarify this link by identifying its causative and underlying pathogenic mechanism(s):
3.1) To elucidate in the HIS mouse model the causative effect of HIV infection on metabolic changes which underlie certain AANCC in persons living with HIV.
3.2) To elucidate in the HIS mouse model the potential causative effect of cART on metabolic changes which underlie certain AANCC in persons living with HIV.
3.3) To clarify a number of possible pathogenic mechanisms, including the possible induction of an inflammation associated accelerated ageing phenol-type, underlying the causative link between HIV and AANCC through the use of a comprehensive range of biomarkers reflecting these mechanisms, in samples obtained from both the HIS mouse model and the clinical cohort.
The project is executed through 7 highly interactive and interdependent work packages (WPs). These WPs are geared towards management (WP1); prospective comprehensive standardised assessment of a range of comorbidities, including neurocognitive, within the clinical cohort composed of both HIV-infected patients on cART and uninfected participants (WP2); an in-depth assessment of cerebral parameters through novel neuro-imaging modalities of the brain (WP3); experiments within the HIS mouse model characterising mice with and without HIV-1 infection, and in the absence and presence of cART, with respect to energy and bone metabolism (WP4), as well as assessment of biomarkers, spanning the range of potentially relevant pathogenic pathways and mechanisms underlying the causative link between HIV and AANCC (WP5). Data management and statistical analysis for the COBRA project (bringing in data from the clinical cohort, neuro-imaging, HIS mouse model and biomarker WPs) is coordinated by WP6 and dissemination of results is coordinated by WP7.
Scientific Advisory Board
The COBRA project has a Scientific Advisory Board (SAB) that comprises of representatives from the HIV patient community, in addition to experts on health policy, scientific experts in the area of HIV and co-morbidities, and scientific experts in the area of ageing research.
The SAB’s role is to provide expert advice on key open project decisions, the general philosophy and direction of the project, corrective measures in the content of the work, if necessary, the dissemination and exploitation of the project results, as well as the quality of deliverables and the overall project status.
Scientific Advisory Board Members:
- Dr Mireille Centlivre (UPMC-INSERM, Hôpital de la Pitié Salpêtrière, France)
- Mr Simon Collins (HIV i-Base, UK)
- Prof. Steven Deeks (UCSF, USA)
- Prof. Jan Vijg (Albert Einstein College of Medicine, USA)
- Dr Marco Antônio de Ávila Vitória (WHO, Switzerland)